With approximately 2% of the world population infected, Hepatitis C Virus (HCV) has emerged as a significant public health problem creating a significant medical, social, and economic burden. Between 70- 90% of those infected fail to clear the virus and remain chronically infected with the likelihood of progression to persistent hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). As a result, HCV-associated liver disease is the leading cause of liver transplantation in the United States. At this time, no preventative vaccine is available, and only 20-30% of chronically infected patients respond to the currently available therapy. Hence, there is a pressing need for a preventative vaccine and alternative treatment options. Unfortunately, research efforts to understand, and thus combat, this infection have been hindered by the lack of robust tissue culture replication systems and small animal models. While the recent development of the in vitro HCV replicon system has overcome some of these limitations, small animal models are still needed for the study of viral-host interactions to assess the pathological effects of the virus and to better understand HCV immunology (e.g. the immunological and virological basis of recovery versus persistence), as well as for testing the in vivo potential of physiological and pharmacological agents for controlling HCV infection. Therefore, the objective of this exploratory proposal is to create mouse models capable of expressing, and potentially replicating, HCV. Initial efforts will focus on the use of selectable HCV replicons, which have proven to be an efficient HCV replication system. However, the mouse-adaptation information gained in these studies may subsequently allow for the development of analogous models that replicate native HCV genomes. The Specific Aims to be addressed are: 1) determine if HCV species tropism can be altered by adapting currently available HCV replicons to replicate in mouse hepatocytes; 2) determine if a murine model of acute HCV can be established by transient T7-driven expression of HCV construct(s) in vivo; and 3) determine if stable RNA Polymerase I-driven expression of HCV construct(s) can serve as a chronic murine model of HCV in vivo.